The present invention relates to a composition for iontophoresis and a device structure using it, more specifically, a composition for iontophoresis to deliver an active ingredient to an organism safely and efficiently using electric driving power and a device structure using it.
Iontophoresis is an accelerating system for transdermal absorption using electricity as an outside stimulus. The principal is that it accelerates penetration of the drug's molecules through the skin barrier based on the moving power of positively charged molecules and negatively charged molecules from the anode to the cathode and from the cathode to the anode, respectively, in the electric field generated between the anode and the cathode mainly by energizing with current (see Journal of Controlled Release, vol. 18, 213-220, 1992; Advanced Drug Delivery Review, 119, 1992; Pharmaceutical Research, vol. 3, pp. 318-326, 1986).
Iontophoresis is a method of making the charged drugs be absorbed in the body positively by electrochemical potential, for example, positively charged drugs are administered to the skin from the anode side. In this case, because the electricity flows through attached organs such as sweat glands and hair follicles which have less electric resistance in the horny layer, it is considered that drugs are delivered mainly through these channels to the epidermis, thereafter spread in the living epidermis, and move to the dermis or the vessel system. In addition, non-charged materials become to move by ions in the solvent through moving of water by the electric field. Thus, in the iontophoresis, electric repulsion and electric penetration play a significant role in addition to the passive diffusion for drug absorption.
On the other hand, it was found that pharmacokinetic control is important for the drugs which show potent bioactivity at a very small quantity and the system being capable for responding for strict dosing control has been required in order to control the adverse reactions to the minimum as well as to make drug efficacy show to the maximum. For example, synthesized narcotic analgesics have only narrow therapeutic range because they have not only a potent analgetic action but also cause significant adverse reactions such as respiratory depression. Calcitonin has an inhibitory action to bone quantity reduction and is used for treating osteoporosis or Paget's disease. The excessive dosing, however, cause the adverse reactions such as anorexia while they are needed to be frequently administered repetitively to increase their therapeutic effect. Most of the drugs are known, however, to be not absorbable since they are decomposed by digestive juices in the gastrointestinal tracts or hydrolized by decomposing enzymes of the gastrointestinal walls. Therefore, as for administration of these drugs, injection is usually conducted to avoid adverse reactions and because adequate efficacy control can not be expected by oral administration. Injections, however, give much pain to patients and become a burden since they can not be self-administered, even more so particularly in the case of the above described Calcitonin which is needed to be frequently administered repetitively.
Iontophoresis has been studied energetically as a new drug delivery system which can respond for such drug administration in the pharmaceutical field. That is, developing the drugs conventionally capable of being administered only as a injection to the formulation capable of being self-administered will allow medical treatment at home. Further, it is considered that particularly in supplementary therapies of endogeneous compounds, more effective drug therapy can be realized taking the circadian rhythm of the living body into account since optional absorption patterns can be generated by controlling the energizing time precisely. Absorption control is also possible by controlling values of electric current.
General structure in the iontophoresis comprises a power source device, the electrodes of the electrically conductive layer connected to the power source device and the electrodes of the electrolyte reservoir. Further, the electrodes of the electrically conductive layer comprise electrodes and an electrically conductive layer, herein the electrode material and preparation of the electrically conductive layer affect greatly the drug efficacy. In order to design an effective drug delivery system in the iontophoresis, the physicochemical factors in the preparation, in particular, ionic strength, competitive ion species, pH, molecular weight (size), concentration and the number of charges and the like in the preparation, are particularly significant as a pharmaceutical approach. Particularly, the electrodes of the electrically conductive layer add the absorption and stability of drugs and stability of the administrated sites while pH of the preparation of electrically conductive layer is a significant factor in order to make iontophoresis effective at the maximum.
Influences of pH on the drug absorption are shown in many references, e.g., Advanced Drug Delivery Review, vol. 18, pp. 379-394, 1996. As a conventional means of iontophoresis, it is described that the drug delivery efficiency with electric current is elevated by increasing the drug ratio in the dissociation state. However, it is known that the materials in the preparation to control the pH include the ion species which have the similar polarity to the drug (competitive ions) causing to reduce the drug delivery ratio substantially.
Further, Japanese Patent Laid-Open Publication No. 9-235230 discloses that pH is adjusted to weak acid region by adding an organic acid to improve the stability of prostaglandin E1 in the electrically conductive layer for iontophoresis. The organic acids are, however, polar materials similar to prostaglandin E1, therefore they can not avoid competition with the drugs when used together.
Further, Japanese Patent Laid-Open Publication No. 9-504191 discloses that the cathode reservoir is adjusted to less than pH 4 and the anode reservoir is adjusted to pH 4-10 in order to reduce stimulation and resistance to skin. As pH adjusting materials or buffer agents used for these purposes, acidic or basic materials with low molecular weight are described. These pH adjusting materials or buffer agents have approximately similar or below the molecular weight of the drugs, therefore they have the problem that they lower the drug delivery rate and reduce the drug absorption when being existed together with drugs.
On the other hand, the study on composition for iontophoresis has proceeded and WO No. 96/34,597 discloses a pH adjusting method using an anion-exchange resin or a cation-exchange resin, e.g. it is disclosed that pH adjustment in the solution containing a drug is conducted with pretreatment by using a hydroxide of the anion-exchange resin as a pH adjusting agent for the solution containing a cationic drug and using the cation-exchange resin having an acidic region as the pH adjusting agent for the solution containing a anionic drug. These operation of pH adjustment is, however, complicated and not practical in terms of quality assurance owing to drug adhesion to the resin, or the like.
Further, in iontophoresis using inactive electrodes such as carbon, platinum and titanium, hydrogen ions and oxygen gas generate at the anode side, and hydroxyl ions and hydrogen gas generate at the cathode side during energizing with current. Thus, at the cathode side, pH of the electrically conductive layer rapidly increases during energizing resulting in reduction of the drug delivery rate and therefore extreme reduction of drug absorption.
On the other hand, in the iontophoresis using active electrodes represented as silver and silver chloride, oxidation or reduction occurs at the voltage lower than that for water electrolysis during energizing. At the anode side, silver electrode is usually used and the electrically conductive layer contains the counter materials such as a chloride ion required for the oxidation or reduction with electrodes. That is, the metal ions (e.g., silver ions) eluted from the anode side during energizing react with the counter ions (e.g., a chloride ion in chloride salts such as sodium chloride and quaternary ammonium chloride such as cholestyramine) contained in the electrically conductive layer, and generate insoluble precipitate (e.g. silver chloride). These practically down-regulate the metal ions' transfer to the skin followed by less generation of protons compared with the case of inactive electrodes, thus they have also high level of safety to the skin. Although proton transfer to the skin is less than the case of inactive electrodes, protons in the electrically conductive layer (containing protons depending on the reservoir's pH) at the anode side gradually transfer to the skin during energizing with current causing pH elevation of the electrically conductive layer. This changes dissociation of the drug and affects the drug absorption particularly with long time energizing with current. No solution has been found yet for means to control those pH changes occurred during energizing with current.
Further, in Japanese Patent Laid-Open Publication No. 7-213628, aminoacryl methacrylate copolymer is described as an example of a film base for the purpose of controlling the drug release. The function is, however, limited to the drug release control and there is no description about the composition for iontophoresis for effective delivery of the drug.
Therefore, the purpose of the present invention is to provide a composition for iontophoresis and the device structure which enables to maintain stable drug absorption without decreasing the drug transfer rate.